1. Field of the Invention
The present invention relates to a continuous process for the cyanation of hydrogenated β-ketoesters.
2. Background Art
Cyanated, hydrogenated β-ketoesters are useful as pharmaceutical intermediates. One particularly useful intermediate is (R)-ethyl-4-cyano-3-hydroxybutyric acid ester of the formula (1)
which is used in the preparation of hypolipidernic agents. There have been a number of reports of the preparation of this compound, and of compounds of this type. For example, JP-A-2001114739 discloses a method for producing lower alkyl esters of (R)-4-cyano-3-hydroxybutyric acid from lower alkyl esters of (S)-4-halogen-3-hydroxybutyric acid by means of a cyanation reaction which comprises carrying out a distillation after filtering an organic solvent phase obtained by extracting and separating the lower alkyl ester of the (R)-4-cyano-3-hydroxybutyric acid from a reaction liquid after cyanation.
JP-A-19970254804 discloses a method for purifying a crude (R)-4-cyano-3-hydroxybutyric acid lower alkyl ester, formed from the cyanation of an (S)-4-chloro-3-hydroxybutyric acid lower alkyl ester by distillation in the presence of a solvent. Japanese Patent No. 2001302607 discloses a process for the cyanation of a halogenohydroxybutyrate at from 90° C. to 120° C. in an organic solvent or mixed aqueous organic solvent.
JP-A-19990018144 discloses a method for producing a lower alkyl ester of (R)-4-cyano-3-hydroxybutyric acid comprising carrying out a cyanation reaction on an (S)-4-halogeno-3-hydroxybutyric acid and then adding an acid and regulating the pH of the reaction solution.
JP-A-2001122841 discloses a method for producing (R)4-cyano-3-hydroxybutyric acid lower allyl ester comprising cyanation of the corresponding (S)-4-halogeno-3-hydroxybutyric acid lower alkyl ester and then extracting the reaction product several times using an organic solvent.
Japanese Patent No. 2001114738 discloses a method for the cyanation of (S)-4-halogeno-3-hydroxybutyric acid lower alkyl esters and extraction of the reaction product with organic solvent.
JP-A-2001114739 discloses a process for the manufacture of (R)-4-cyano-3-hydroxybutyric acid lower alkyl esters from the cyanation of (S)-4-halo-3-hydroxybutyric acid lower alkyl esters, followed by extracting the ester formed from the reaction solution, filtering the organic solvent phase and distilling.
WO-A-00/46186 discloses a process for preparing (R)-4-cyano-3-hydroxybutyric acid ester derivatives by cyanation and sequential esterification (S)-3,4-epoxybutyric acid salt as a starting material.
Despite extensive investigation of methods for producing (R)-4-cyano-3-hydroxybutyric acid ester derivatives, there remains a need for an improved commercial process. Each of the prior art processes suffer from one or more of the following disadvantages: poor yield; low conversion rate; use of expensive and/or unnecessary reagents or solvents; purification problems; lack of stereoselectivety; suitability only for laboratory scale preparation; or other unsuitability for commercial scale operation. It is therefore an object of the present invention to provide an improved process for the cyanation of hydrogenated β-ketoesters, in particular a continuous process for such cyanation which may be operated on a commercial scale.